Ebocess



Patented Aug. 3, 1948 eroe i 'fWilhlm rwven'mer, .'iMontclair, VN. J.

, assigner "to Hoffmann-La. Roche Inc.,"Nutley,`N., J., a c'orporaton of New Jers "NoDrawng. I'App licatiomSeptemberIZS,21945,

yclic" aliphatic al'dehyde, 'eten-e, "or `a cycloaliplratic nsaturated 4carbonyl ,Theproductf-offthefreactioniwithwcroton .ahle- Ahytefin the; preceding;`

The-zlnsatur-ated aldehydes fappearztobefmore `ufexactiile:Ethanthe acorrespon'din'gflsaturated Idehydes,an*dnane qn'eferred forfthatrreason in 'eertain fsyntheses.

By-weacting rbarbiturlc acid .fwith :saturated ketone, `the plies:

(Iv) H N- oo 11N-co rom anf'examplei -o'f A*an* unsaturated `fketcinje; I'set following illustrative @equation fap- *Y Illustrativeexamples zofealdehydes fandketenes which can be employed in my novel process are: acetone, n butyraldhyde, isobutyraldehyde, m'e'thylethylketonemethylen#propyl-fketoneadithyL-ketone, nhexalldhyde, :fmethyl -lisobutylketone, acetalfdeh-yde, 1cyclopentazmna cyclehexianpne, lanesity'l f oxide, Land rerntenfaldehyde.

lfThe' reactionf is carriedfeutf in generalifbyimixlling.rbarliturica'eidwith fa'frnelecular-fiquantity@of fthe `.Tzadldhydenor ketone, prferab'lyflin athe. presence ef fa '-suitab1e *fslv-ent, lfai-fd 'subjecting the fm'xturefto catalytic fhydr'ogen'ation. kThe ftem- 45 -lperature sat ewhichl the reactions-.is =carriedee1t'is preferably about 80-110 C., but highenerirlawer temperatures can lam-employed.

The pressure may varywithin wide limits. A "range `el200=160'0p.';s; 4i. "is suitzbIe Injgeneral, '50 "nigh :pressures speed `up the reaction. While condensing-agents are not v`essential, they may be z'iesirab'le "in certain instances. "Ammonium acetate "and fethylene diamine 'acetate are set forthassuitabIeforwemurpose.

"The reaction A'is preferentially carried 'out v"rn 'Lio drogenated at 100 tone, and 0.5 part of hydrochloric acid.

the presence of a suitable solvent. In the preparation of -isopropyl barbituric acid, acetone is employed as the ketone reactant. In this synthesis, an excess of acetone can be utilized as the solvent. However, lower aliphatic alcohols, such as methanol and ethanol, are particularly useful solvents. Additionally," acetic acid and water are valuable as solvents. The quantity of solvent is variable, as shown in the examplesgiven hereinafter. Mixed solvents can be used. As catalysts, I may employ nickel, such as Raney nickel, or a noble palladium on chorcoal. In general I employ about per cent. of nickel catalyst, or 0.5-1 per f cent. of palladium, based upon the weight of barbituric acid used.

The following examples are Apresented to illustrate various embodiments of my invention` the examples However, it will be understood that are intended to be typical of the broad'reactions set out above, and the particular reagents employed, as well as the conditions under which the reactions are carried out, are not to be taken as restrictive in nature. The products may be prepared and used either in a pure or an impure state.

Example 1 22.4 parts by weight of barbituric acid, parts of acetone, 30 parts of absolute alcohol, and l part of palladium-charcoal (10% Pd) Y are hyand 700 lbs. pressure until the hydrogen absorption is complete. The mixture is thendiluted with a suicientamount oi alcohol to dissolve the formed -isopropyl-barbituric acid at 80, filtered from the catalyst, and allowed to cool. 5-isopropyl-barbituric acid separates in bright shiny` crystals of{M.P. 212-213". Evaporation of the mother liquor yields an additional amount.

Eample 2 13fparts of barbitric acid, 50 parts of acepalladium-charcoal (10% Pd) are hydrogenated at 110 and 800 lbs. pressure. Most of the -isopropyl-barbituric acid formed crystallizes on cooling. It is filtered. To remove the catalyst, the crystals are dissolved in aqueous sodium hydroxide, and the solution filtered. -'The colorless filtrate is acidified with separates in colorless crystals of M. P. 212213.

An additional amount is obtained by evaporation of the acetone mother liquor. ,j

Example 3 l 13 parts barbituric acid, 10 parts of acetone,

.40 parts of water, and:v 0.5` part of palladiumcharcoal (10%) are hydrogenatedv at 100 and and 500 lbs.- pressure. Most of the 5-isopropylbarbituric acid is crystallized after the reaction.

filtered from the catalyst. Addition of dilute -isopropyl-barbituric acidmetal catalyst, such as .600 lbs.v.pressure.-

parts of methanol are added,the mixture reuxed sulfuric acid precipitates 5-isopropyl-barbiturc acid. The original mother liquor on evaporation yields an additional amount of -isopropylbarbituric acid.

Eample 5 13 parts of barbituric acid, 50 parts Vof acetone,

and 2 parts of Raney nickel catalyst are hydrogenated at 90 and '700 lbs. pressure. Water is vadded and the acetone distilled off. After removal of the acetone, sodium hydroxide is added todissolve the'crystals. .The solution is filtered from the catalyst. The filtrate is acidied. 5-

y isopropyl-barbituric acid separates and is filtered.

l Example 6 13 parts of barbituric acid, 10 parts of acetone,

" 30 parts of acetic acid, and 1 part of palladiumcharcoal (10%) are hydrogenated at 100 and 500lbs. pressure. After hydrogenation, enough acetic acid is added to dissolve the crystals at 100, theA solution filtered and cooled. 5-isopropyl-barbituric acid is obtained in good yield.

YEssai/mile 7 13 parts of barbituric acid, l0 parts of acetone, 40 parts of water, 2 partsof acetic acid, and 2 parts of RaneyY nickel arehydrogenated at 4001bs. and 90. After the hydrogenation, the mixture is boiled and enough water is added to dissolve the crystals. The solution is filtered from the catalyst and cooled. 5-isopropyl-barbituric acid separates in colorless plates.

Example 8 26 parts of barbituric acid, 20 parts of acetone, parts ofl methanol, 1 part of ammonium acetate, and 2 parts of Raney metal are hydrogenated at and 400 lbs. pressure. After the hydrogenation, most of the -isopropyl-barbituric acid has separated. It is filtered and recrystallized from water.

`Errample 9 13 parts of barbituric acid, 10 parts-of acetone,

30 parts of methanol, and 0.5 part of platinum oxide are hydrogenated at and 400 lbs. pressure. After the hydrogenatomthe r-isopropylbarbituric acid is extracted with boiling methanol. The hot solution is filtered and evaporated. 5-isopropyl-barbituric acid remains and is recrystallized from'water or ethanol.

- Example 10 V26 parts of ybarbturic acid, '16 parts of n-butyraldehyde, 1001parts of methanol,and 1 part of palladium-charcoal are hydrogenated at 100 and AfterV the hydrogen'ation,4 400 and filtered while hot. On cooling, -n-butylbarbituric acid separates. M.`P. 208-210,

Example 11" 25 parts of barbituric acid, 16 parts of isobutyraldehyde, 100 parts of methanol, 1 part of ammonium acetate, and l part of palladium-charcoal are hydrogenated at 100 lbs.pressure and 100. After coolingmost of the 5-isobutyl-barbituric acid is crystallized. It is filtered and recrystallized from ethanol. Pure -isobutyl- .,barbituricacid of E235-236 is obtained. v

Example 12 25 parts of barbituric acid, 18 parts of methylethyl-ketone, parts of methanol, 2 parts of ammonium acetate, and 1 part of palladiumcharcoal (10% Pd) arehydrogenated att90 and s 1:0001 lbs pressures.` nesultingxsolutizon is lltened: from thecatalyst.. The filtrate is distilled to' dryness; v5.-sem-butylb'ariflituric acidi` remains behind and. isreerystalflized fronrmethanol. pureacidishows M. P. 1193-194". I

` Emmplefl' Y I i 25 pantser. barbiturieacidy. 20 parts of methyln-propyl-ketone, 70 parts of methanol,andv 1 part `of;.-palladium-charcoal (20%) are hydrogenalted artilllf and 600v lbs.. pressure. 'The mixture is diluted with methanol, neil-faxed andv filtered while hot. The solution is evaporated and the residuerecrystallized from: water or fromalcohol, yielding -(a-methylbutyl)--barbituric aci-dI of M. P. 166. Insteadof methanol, acetic .acidlcan b e used as a solvent. v-

1 par-ts: off barbituric 13pm-tts. of ,diethylketone,.'7.0 partsof methanol, andi-` part of pal-la.-

dium-charcoal are hydrogenated at`90 and 600 lbs. pressure. Thefmi-xturey is refluxed. after addition of 300 parts of methanol, and ltered. After evaporation ofthe solution, -(diethyle methyl) -barbituric acidi ot P. 11M-195 is obtained. l

. Example 1.5

lpartsof barbituric acid, 1l parts of n-hexaldehyde, 35 parts of methanol, and 1 part of palladium-charcoal are hydrogenated at 100 and 500 lbs. pressure. The resulting mixture is diluted with 150 parts of methanol, heated to boiling, and filtered hot. The ltrate is evaporated, and the residue is recrystallized from alcohol. Pure 5-n-hexyl-barbituric acid of M. P. 187188 is obtained.

Example 16 Example 17 parts of barbituric acid, 15 parts of acetaldehyde, 80 parts of alcohol, and 1 part of palladiumcharcoal are hydrogenated at 400 lbs. and 100. Alcohol is added, the mixture heated to solution, and ltered from the catalyst. On cooling, 5- ethyl-barbituric acid, M. P. 190191, separates.

Example 18 13 parts of barbituric acid, 10 parts of cyclopentanone, parts of methanol, and 1 part of palladium-charcoal (10%) are hydrogenated at 100 and 500 lbs. pressure. 'I'he partly crystallized mixture is diluted with methanol, heated to solution, and filtered. On cooling, 5-cyc1opentylbarbituric acid separates. Recrystallization from alcohol yields the pure acid of M. P. 220-221.

Example 19 13 parts of barbituric acid, 12 parts of cyclohexanone, 50 parts of alcohol, and 1 part of palladium-charcoal (5%) are hydrogenated at 100 and 250 lbs. pressure. The reaction product is largely crystallized. It is ltered and dissolved in dilute sodium hydroxide. The solution is lilteredriromrthe catalyst; and'. the nitrate: acidtned with dilute sulfuric acid. 5cyc1oliexylbarbitunic acidiseparates and is recrystallized.v from? alcohol.

1'3 parts oi' barbituric'acid, 8 parts ofl crotch aldehyde, 3" 'parts "of palladium-charcoal (2%)', and 31)'A parts'. of methanolv are hydrogenatedat gli-10030'. and`600V lbs. pressure for 15 hou/rs.E The is reflux'edA with'` 300 partsv of"me'thanol an'dlter'e'd hot from'the catalyst. The clear, colorless filtrate is evaporated to dryness.` 5-nbutyl-barbituricacijd separatesV crystalline. It is reer;fst-al1'iz'edv from water; The pure acid shows and is identical with the product prepared'accordingto Example 1 0;` f I Example .21I 'ze parts of barbitiiricacie, 16 parts ofmesityl oxyde; 'l part'ofv Ypalladium-cha-rcoa1 (2%)', vand 35- pa-rts ofm'e'thanol'fare hydrogenatedv at 90' C. and-87'0 lbs. pressure for 20 hours. The mixture is' lteredand the filtrate is evaporatedto dryness'. The residue Vis recrystal'li'zed from Water, giv'm'g acid, melting at 199 C'.

Y Example 22 13l parts of barbituric aci'd'f,8 parts of acetone, 24"y parts of' methanol, 1' part of ethylenediamine, 2 parts of acetic acid, and part of palladiumcharcoal (20%) are hydrogenated at 100 and 700 lbs. pressure for 5 hours. The solution is diluted with methanol until most of the crystals dissolve on reiiuxing. It is ltered hot, leaving 3 parts residue which on dissolving and acidification yields 1.2 parts of unchanged barbituric acid. From the methanol solution, 9.1 parts of crude -isopropyl-barbituric acid, M. P. 209-211", crystallizes on cooling. 0.8 part of M. P. 20S-208, is isolated from the remaining mother liquor.

In the foregoing examples, the term parts will be understood to mean parts by weight.

I claim:

1. The process of making barbituric acids substituted in the 5position by a single hydrocarbon radical which comprises hydrogenating barbituric acid in the presence of at least one molecular quantity of a member of the group consisting of aliphatic aldehydes, aliphatic ketones, and cycloaliphatic ketones so as to produce the said barbituric acids.

2. The process of making -monoalkyl-barbituric acids which comprises hydrogenating barbituric acid in the presence of at least one molecular quantity of an aliphatic aldehyde so as to produce the said barbituric acids.

3. The process of making 5-monoalkyl-barbituric acids which comprises hydrogenating barbituric acid in the presence of at least one molecular quantity of an aliphatic ketone so as to produce the said barbituric acids.

4. The process of making -monoalkyl-barbituric acids which comprises hydrogenating barbituric acid in the presence of at least one molecular quantity of a saturated aliphatic ketone so as to produce the said barbituric acids.

5. The process of making 5-monoa1kyl-barbituric acids which comprises hydrogenating barbituric acid in the presence of at least one molecular quantity of an unsaturated aliphatic aldehyde so as to produce the said barbituric acids.

6. The process of making -isopropyl-barbituric acids which comprises hydrogenating barbituric acid in the presence of at least one molecfbarbituric acids. v

.ular quantity of acetone so as to produce'v the said .z .7. The process of; making SQQ-methylbutyllbarbituric acid which comprisesV hydrogenating barbituric acid .in :the-,presence of at least one molecular quantity of methyl-n-propyl ketone so as to produce the :said barbituric'-'acid.v

8. 'l'he process 'of making 5-n-butyl-barbituric `acid which comprises hydrogenatng barbituric acid :inthe presenceof at' least one molecular quantity of croton aldehyde Yso as to produce the 'said "barbituric'acid.' 1 y K The process of making barbituric acids substituted in the -position by a single hydrocarbon radical which comprises hydrogenating barbituric acid ih the presence of aisolventzand inthe presence of at least one molecularquantity 'of' a member of the group consisting of aliphatic aldehydes, aliphatic ketones, .and cycloaliphatic il;etor'1` 'e`s Aso as to produce .the said barbituricracids. f. V10; The process ,of making barbituricacds substituted 'in the 5-position by a single hydrocarbon radical which comprises cavltalyticallyV hydro-.- 'genating barbituric acid in `the presence of a hydrogenation catalyst selected from the group consisting of `noble metal catalysts and nickel catalysts, and in the presence of at least one molecular quantity of a' member of the group 4c zqmsisting of ,aliphatic aldehydes, aliphaticgketonesand cycloaliphatic ketcnesso as to produce the: said barbituric acids. 4

1 11.' The process of making barbituric acids substituted in the -position by a single hydrocarbon Aradical-Which comprises catalytically hydrogenating barbituric acidin the presence of 'a palladiumcharcoal catalyst, in. the presence' "of one molecular quantityof a member of the group consisting of aliphatic'aldehyde's, aliphatic ketones, and oycloaliphatic kat-ones so as to produce the said barbituric acids.-

. 12. The process of making barbituric acids substitutedin the -position by a single hydrocarbon A'radical which comprises catalytically hydrogenat 14."The process of'claim 1 2-'in which a condensing agent isemployed. said condensing-agent being a member of the group consisting of ammonium acetate and ethylene diamine acetate.`

l5. The process of claim 12 in which the hydro'- genation catalyst is a palladium-charcoal catalyst.

WILHELM WENNER. 

